Diffuse GI (gastrointestinal) bleeding is a major medical problem following radiation treatments. Angiodysplasia of the intestine is now considered the most frequent cause of major colorectal bleeding being more frequent than diverticular bleeding. Radiation proctosigmoiditis has been studied by Gilinsky et. al. (1983) who found that 35% of patients had moderate GI bleeding and 20% had appreciable bleeding with a significant number of these patients needing operation to remove the affected bowel segment.
Patients suffering from diffuse GI bleeding are currently treated with repeated blood transfusions and surgical resection of the involved segment of the GI tract. A major problem with surgical treatment, however, is that a bowel that has been irradiated does not heal well and the breakdown of a suture line after surgery is a frequent complication, requiring further surgery and the removal of more of the bowel. Also, the dense adhesions that developed following radiation to the pelvis often make it difficult to delineate normal anatomy from pathology, and surgery therefore results in the removal of more bowel than is strictly necessary. In angiodysplasia of the colon, it sometimes is difficult to establish the exact site of bleeding. Sometimes, the small and large bowel are affected concomitantly and establishing the exact extent of resection can be very difficult for the surgeon.
Colonoscopic electro-coagulation and laser therapy are the preferred method of treatment for recurrent bleeding. The incidence of re-bleeding and the need for repeating the procedure varies from 0-34%. Surgical resection is often necessary when bleeding recurs. Occasionally re-bleeding occurs post-resection when the site of bleeding is more extensive that originally thought. In both situations presented, there is a need for a conservative treatment which should work on extensive areas of the GI mucosa.
Conservative treatment (steroid retention enemata) by administration of sulphasalazine and 5-aminosalicylic acid (mesalamine--a gastrointestinal anti-inflammatory used in the treatment of ulcerative colitis) has been tried with variable results in radiation proctitis. In cases of angiodysplasia of the intestine, the use of vasopressin infusions lead to re-bleeding in 21% of cases. Embolisation with Gelfoam has a high risk of re-infarction. These attempts at conservative treatments demonstrate that there has been a long felt need for an alternative to surgical intervention to reduce diffuse GI bleeding.
Erythropoietin (also known as procrit) is a glycoprotein hormone, thought to be produced primarily in the kidneys, which is a stimulating factor for erythropoiesis, the process by which erythrocytes (red blood cells) are formed in the bone marrow. Human erythropoietin has been produced by recombinant technology, and is known as Epoetin.
Erythropoietin is being used successfully in the treatment of anemia of chronic renal failure, anemia of cancer and in HIV patients. It is primarily used to induce production of red blood cells to combat anemia, and not to stop diffuse bleeding. Erythropoietin is known to decrease the bleeding time in uremic (kidney failure) patients. In vitro and in vivo studies on uremic patients have shown an improved platelet endothelial cell interaction, which explains the shortening of the bleeding time, but there are no studies done of the hemostatic mechanism (clotting mechanism) induced by erythropoietin on non-uremic patients. But there has been no recognition prior to the present invention of the significant limitation of GI bleeding that can be achieved by the administration of erythropoietin in uremic or non-uremic patients.
There are three reported cases of Jehovah's witnesses patients who had acute as opposed to chronic blood loss, and bleeding was localized to a small area as opposed to diffuse bleeding with critically low Hgb. The patients refused blood transfusions and were successfully treated with recombinant erythropoietin plus ferrous sulfate, folic acid and vitamin B-12 subcutaneously, which was used for its stimulating effect on the production of red blood cells.
One patient was a 66 year old woman who bled from multiple peptic ulcers. She had melena (passing of black bloody bowel movement) and sycope (passing out) with a Hcrt of 14.5%. Since she refused blood transfusion she was treated with recombinant erythropoietin 20,000 units for three doses followed by 6,500 units up to two weeks. On the 14th day, her Hcrt was 27.1%. The erythropoietin was not administered to contain bleeding, but was administered to increase the hematocrit count by boosting the red cell production only after the bleeding had stopped. Furthermore there's nothing in the publication, "Erythropoietin and Anemia of Gastrointestinal Bleeding in a Jehovah's Witness", Ann. Int. Med. 112, 552 (April 1990), that indicates that erythropoietin would stop diffuse GI bleeding. The thrust of the publication is the use of erythropoietin as a substitute for blood transfusion for Jehovah's Witnesses.
The second case was a four year old black male Jehovah's witness with hematemesis (vomiting of blood) who was found to have a 2.5 cm fundal ulcer and a Hcrt of 19.1. He was treated with Fe Dextran IV 100 mg/day, erythropoietin 50 units/kg IV. On the 8th day, his Hcrt was 22.9 and he was discharged home.
The third and last case presented in the literature was a 14 year old black male who had massive hematemesis (vomiting of blood) following esophageal dilatation for an esophageal stricture. Being a Jehovah's witness, blood transfusion was refused. He underwent surgical repair for G-E tear. The post-operative Hcrt was 14.4. Recombinant Erythropoietin 50 units/kg IV was given. Four days after surgery, his Hcrt was 25.9 and was discharged home on the 9th post-operative day tolerating oral feeding and oral iron supplementation.
In uremic patients, it is known that erythropoietin corrects the prolonged bleeding time after one week of treatment and increases the hemoglobin/Hcrt after two weeks of treatment. But this information has not been previously considered related to the problem of GI bleeding in uremic or non-uremic patients.
In uremic patients on chronic hemodialysis, it has been shown that erythropoietin alpha works on both (1) the primary hemostatic plug formation as well as (2) the coagulation phase. (1) Within the mechanism of the primary hemostatic plug formation, it increases the platelet count, the collagen dependent platelet aggregation and the ristocetin induced platelet aggregation. It produces a rise in blood and platelet serotonin content that is supposed to lead to an improved platelet-endothelial cell interaction also, serotonin produces vasoconstriction. All of these effects lead to a shortening of the bleeding time in uremic patients on chronic hemodialysis.
On the other hand, (2) erythropoietin alpha used in uremic patients on hemodialysis also worked on the coagulation phase by producing decline of the protein C, protein S and anti-thrombin III (which are natural anti-coagulants and their deficiency leads to an enhancement of the coagulation mechanism). All of the findings on uremic patients on hemodialysis provide a scientific basis for the observed effect of erythropoietin alpha in limiting GI bleeding in the non-uremic patients.